PROJECT SUMMARY Depression is prevalent, devastating, and the leading cause of disability worldwide. Compelling evidence from prospective longitudinal and experimental studies implicates inflammation in depression pathogenesis; however, inflammation is neither a necessary component nor a sufficient cause of depression, and there is variability in whether an inflammatory stimulus elicits depressive symptoms. Thus, it is critical to identify predisposing factors that render some individuals susceptible to depression upon exposure to heightened inflammatory states. There is increasing evidence that females may be at risk for inflammation- induced depression; specifically, in comparison to males, females have higher depression prevalence in epidemiological studies, are overrepresented in other diseases with an inflammatory basis, and exhibit greater depressive response to inflammatory challenge in experimental studies. However, it is not clear if this vulnerability is present across the adult lifespan. In particular, sex differences in depression prevalence decrease with older age despite increases in systemic inflammation. The mechanisms underlying this change are not clear, but it is possible there are age-related decreases in affective sensitivity to inflammation among females. To interrogate this hypothesis, the proposed supplemental study will examine affective sensitivity to inflammation in male and female older adults, and in younger and older female adults. Because depression involves dysregulation in negative (e.g., dysphoria) and positive (e.g., anhedonia) domains, which may manifest differently as a function of sex and age, this study will also test for sex and age related differences in negative and positive affective sensitivity to inflammation. In this placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (60-80 y; stratified by sex; n = 80) and younger adults (25-40 y; female; n = 40), we hypothesize that older females will (still) show stronger affective response to inflammatory challenge than older males, and that younger females will show heightened affective response as compared to older females. Specifically, we aim to: 1) examine differences in negative and positive affective response to an inflammatory challenge as a function of sex in older adults; 2) examine differences in negative and positive affective response to an inflammatory challenge as a function of age in female adults; 3) examine the correlation between inflammatory response and affective response to endotoxin according to sex and age. Results will inform the identification of high risk groups who should be prioritized for monitoring of depression in the context of elevated inflammation (e.g., diagnosis with chronic disease) and who may benefit from prevention and treatment efforts that target inflammation. Moreover, this study will characterize the negative and positive affective mechanisms that may contribute to sex and age-related differences in inflammation- induced depression, which will inform the development of optimized pharmacological and psychosocial treatment approaches.